Schizophrenia is a psychiatric condition characterised by positive symptoms, for example hallucinations, delusions, disturbances of thought, paranoia [Andreson, Mod. Probl. Pharmacopsychiatry 24, 73-88 (1990); Peralta et al., Br. J. Psychiatry 161, 335-343 (1992)], negative symptoms, for example apathy which primarily manifests as emotional and motivational deficits and deficits in social interactions, cognitive deficit together with depression.
This complex scheme of symptoms which is observed in schizophrenic patients suggests the existence of dysfunctions at various levels in the brain of these individuals and it is thus difficult to hypothesise that malfunctioning of a single neurotransmitter system could explain the complex pathological picture of the disease.
The until recently accepted hypothesis suggested hyperactivity of the dopaminergic system as the primary cause of the clinical manifestations of schizophrenia. This hypothesis was largely derived from the observation that amphetamine brings about positive symptoms which resemble those present in paranoid patients; this symptomatology is brought about by increased dopaminergic neurotransmission in the central nervous system (CNS) (Sayed et al., Psychopharmacol. Bull. 19, 283-288 (1983)].
However, many schizophrenic patients and in particular those exhibiting predominantly negative symptoms do not respond adequately to treatment with dopamine antagonist drugs, so demonstrating that the dopaminergic model can only provide a partial explanation of the complexity of the disease.
Functional anatomical studies have revealed morphometric changes in the cerebral cortex of schizophrenic individuals, these changes probably arising from modified cortical development. Glutamate is the primary neurotransmitter at this level and it is thus probable that dysfunction of the glutamatergic pathways may well play an important part in schizophrenia as it does in bipolar disorders. The dopaminergic and glutamatergic hypotheses are not mutually exclusive because there are major functional interactions between these two neurotransmitter systems.
One limitation of preclinical studies into novel molecules with potential antipsychotic activity is the limited availability of animal models capable of meaningfully reproducing a complex pathological picture such as that presented by schizophrenia. Despite this, there are models which can sufficiently effectively reproduce the symptoms of such disease with the aim of assessing the pharmacological activity of the potential candidate drug in specific functional changes.
On the basis of published preclinical data, the compound neboglamine (CR 2249) has shown that it possesses considerable modulating properties for the (strychnine-insensitive) glycine site coupled to the NMDA receptor complex [Lanza et al., Neuropharmacology 36, 1057-64 (1997)] together with interesting properties promoting memory and learning in various animal models [Garofalo et al. J. Pharm. Pharmacol. 48, 1290-97 (1996)].
The facilitatory activity exerted by neboglamine at the level of the NMDA receptor complex should be of therapeutic utility under conditions involving glutamatergic hypofunctionality, which, as explained above, may contribute to the negative symptomatological picture of schizophrenia.